Abstract
SummaryHuman ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.
Highlights
Accessibility to the DNA during many vital cellular transactions is regulated in part by ATP-dependent chromatin-remodeling enzymes (Bartholomew, 2014; Becker and Workman, 2013; Bowman, 2010; Clapier and Cairns, 2009; Narlikar et al, 2013)
ALC1 is unique among remodelers in that it possesses a macro domain that can selectively bind to poly(ADP-ribose) (PAR) (Ahel et al, 2009; Gottschalk et al, 2009) synthesized by PAR polymerases (PARPs) at DNA damage sites (Hassa et al, 2006; Lindahl et al, 1995; Satoh and Lindahl, 1992)
Upon binding PARylated PARP1, the macro domain of ALC1 is displaced from its ATPase, which we propose is a key step in the selective activation of ALC1 upon recruitment to DNA damage sites
Summary
Accessibility to the DNA during many vital cellular transactions is regulated in part by ATP-dependent chromatin-remodeling enzymes (remodelers) (Bartholomew, 2014; Becker and Workman, 2013; Bowman, 2010; Clapier and Cairns, 2009; Narlikar et al, 2013). These remodelers typically possess a catalytic subunit that encompasses a conserved Snf family (sucrose nonfermenter 2) ATPase and flanking domains that can give rise to distinct remodeling outcomes (Flaus et al, 2006; Narlikar et al, 2013). The molecular basis for such a mechanism remains elusive
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